Abstract Body: Both the loss of ovarian function and the presence of cardiovascular disease promote the development of Alzheimer’s disease and vascular dementia. In particular, hypertension and arterial stiffness are associated with cognitive impairment by reducing neurovascular coupling (NVC) and dendritic plasticity, but whether estrogen improves brain health in the presence of cardiovascular disease is undetermined. Our current study hypothesized that estrogen enhances NVC in normotensive but not hypertensive conditions. Female C57BL/6J mice were ovariectomized at 10.5 months of age to emulate menopause in humans and randomized to vehicle or 17β-estradiol (E2) treatments. In addition, mice were randomized to control or hypertension via infusion of angiotensin II (AngII; 700 ng/kg/min). Tail cuff plethysmography and pulse wave velocity were used to monitor blood pressure and arterial stiffness, while cranial window two-photon microscopy was used to measure vasodilation of penetrating arterioles in the somatosensory cortex. In the absence of AngII, E2 did not impact blood pressure or arterial stiffness but improved NVC (P=0.01). AngII induced hypertension in the vehicle group (P<0.001), but not in the E2 group (P=0.78). Arterial stiffness, measured as pulse wave velocity, followed the same pattern as blood pressure, with AngII increasing stiffness in the vehicle group (P=0.02), but not the E2 group (P=0.65). AngII similarly impaired NVC in both vehicle and E2 groups (P=0.91), essentially removing any benefit of estrogen. In conclusion, E2 improved NVC in control conditions but not in the presence of Ang II, even though E2 was protective against AngII-induced hypertension and arterial stiffness. These data indicate that E2 may not provide protection against Alzheimer’s disease and vascular dementia in women with cardiovascular risk factors. Future studies will investigate the impact of AngII and E2 on dendritic plasticity and cognitive function. Research funding provided by NIH P01AG071746.